More than 74 million American adults have hypertension, or high blood pressure, which has no noticeable symptoms but results in greater risk for stroke, heart attack, or other heart damage. Membrane bound Atrial Natriuretic Factor Receptor Guanylate Cyclase (ANF-RGC) is one of the major physiological regulators of cardiovascular and renal homeostasis and, in particular, has been linked with blood pressure regulation. It acts as the surface receptor of the two natriuretic peptide hormones, atrial natriuretic factor (ANF) and B-type natriuretic peptide (BNP). Upon binding of these hormones, ANF-RGC initiates a cascade of structural changes, ultimately transmitted through the transmembrane domain to the intracellular portion of the protein. At the C-terminal catalytic domain, it is translated into the generation of cyclic GMP. Cyclic GMP then serves as the second messenger for downstream control of cardiovascular and renal homeostasis, including relaxation of blood vessels and cardiac smooth muscle and decreasing blood pressure.
ANF-RGC machinery and its response to ANF/BNP-ligand stimulation is complex and requires co-binding of both the extracellular ligand (e.g. ANF or BNP) and intracellular ATP. The binding of both causes allosteric modifications of the ANF-RGC protein that ultimately leads to activation of its catalytic domain. An ATP-signal transmitting motif, ATP-ST, is critical for the transduction of the ANF (or BNP) and ATP signals into the production of the cyclic GMP. The ATP-ST constitutes a 7-amino acid motif spanning amino acids 669-675 of the ANF-RGC protein and is contained within the ATP-regulated module (ARM) of the ANF-RGC protein. It controls almost all (˜95%) of the total stimulated activity of ANF-RGC, i.e. cyclic GMP production.
Accordingly, the ANF-RGC protein, particularly the ARM and ATP-ST domain, presents an attractive target for studying the ANF-RGC-mediated cyclic GMP pathway and its effects on cardiovascular and/or renal homeostasis. It also presents an attractive target for potential therapeutic agents for treating diseases or disorders associated with the ANF-RGC-mediated cyclic GMP pathway, such as, but not limited to, hypertension.